JP2016508503A - 呼吸器合胞体ウイルスfタンパク質エピトープ - Google Patents
呼吸器合胞体ウイルスfタンパク質エピトープ Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/12—Viral antigens
- A61K39/155—Paramyxoviridae, e.g. parainfluenza virus
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- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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- C12N2760/00011—Details
- C12N2760/18011—Paramyxoviridae
- C12N2760/18511—Pneumovirus, e.g. human respiratory syncytial virus
- C12N2760/18534—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Abstract
Description
本出願と共に提出されたASCIIテキストファイルで電子的に提出された配列表の内容(名称:sequencelisting_ascii.txt;サイズ:31.3キロバイト;及び作成日:2013年3月14日)は、参照によりその全内容が本明細書に組み入れられるものとする。
本発明は呼吸器合胞体ウイルスFタンパク質エピトープに関する。
本開示において、「1つの(a)」又は「1つの(an)」実体という語は、1つ以上のその実体;例えば、「1つのポリヌクレオチド(a polynucleotide)」は、1つ以上のポリヌクレオチドを意味することを理解されたい。従って、「1つの(a)」(又は「1つの(an)」)、「1つ以上の」、及び「少なくとも1つ」は、本明細書で互換的に使用することができる。
呼吸器合胞体ウイルス(RSV)は、パラミクソウイルス(Paramyxoviridae)科のニューモウイルス(Pneumovirus)属に属する。ウイルスゲノムは、11のタンパク質をコードする負の極性の一本鎖RNA分子からなる。これらのタンパク質のうちの2つは、ビリオンの主要表面糖タンパク質、即ち(i)ウイルスの細胞表面への結合を媒介する付着タンパク質(G)、及び(ii)ウイルスの侵入の際にウイルスと細胞膜との融合を促進するとともに、感染細胞の膜と周囲細胞との融合も促進して合胞体を形成する融合タンパク質(F)である。2つの主要な抗原グループ、AとBは、最も優勢なグループAと、主にGタンパク質における差異によって区別される。
株A2由来のRSV−A Fタンパク質配列(配列番号1)
>gi|2627305|gb|AAB86664.1|融合F糖タンパク質前駆体[ヒト呼吸器合胞体ウイルス]
>gi|222565|dbj|BAA00240.1|融合タンパク質前駆体[ヒト呼吸器合胞体ウイルス]
「モノクローナル抗体D25」又は「mAb D25」という語は、参照によりその全内容が本明細書に組み入れられる国際公開第2008/147196号パンフレットに既に記載されている、「D25」と称される抗RSVモノクローナル抗体並びにその抗原結合断片、変異体、誘導体、及び/又は類似体を指す。
実施例で実証されるように、mAb D25は、融合前形態のRSV Fタンパク質の高次構造エピトープに結合する。D25は、可溶性Fタンパク質にはあまり結合しない。D25は、未固定RSV感染細胞の表面に結合するが、固定感染細胞には結合しない。加えて、D25は、加熱された、即ち、RSV Fタンパク質が融合後高次構造をとるようになるインビトロ処置を受けた感染細胞の表面には結合しない。
1A.HR1xHR2(配列番号3)− RSV A2 Fタンパク質のアミノ酸153−221(太線)及びアミノ酸476−520(イタリック体)を含む。
D25は融合前形態のRSV−Fタンパク質を発現する細胞に結合する
抗体D25によって認識される中和エピトープに結合するための要件を理解するため、多数の戦略を利用した。
D25は熱処理RSV−Fタンパク質に結合しない
D25が、融合前RSV−Fタンパク質の高次構造エピトープのみを認識することを確認するために、Eu3+標識D25の結合を、融合前形態を示す非加熱デノボRSV−Fタンパク質、又は融合後形態をとる加熱(反転)RSV−Fタンパク質について試験した。
バイオレイヤー干渉分析によるD25結合試験
バイオレイヤー干渉分析を使用して、D25のRSV−Fタンパク質への結合に対する、加熱又は4℃での長期保存によるRSV−Fタンパク質の高次構造の変化の影響を決定した。
D25は抗6へリックスバンドル抗体と競合しない
特に、D25が、十分に特徴付けられたエピトープ領域を有する他のRSV抗体と競合するか否かを試験するために、バイオレイヤー干渉分析を使用して、D25エピトープの位置をさらに決定した。
D25は抗原部位A、B、又はCに結合する抗体と競合しない
RSV−Fタンパク質は、一般に述べられている少なくとも6つの異なる中和抗原部位を有する。既に同定された抗RSVモノクローナル抗体、パリビズマブ(SYNAGIS(登録商標))、モタビズマブ、1153、1121、13/19、92−11C、131−2A、1331H、及び1308Fは、図6に例示されているように十分に特徴付けられた抗原部位A/II、B/I、又はCに結合する。
D25エピトープのマッピング
この実施例は、RSF−Fタンパク質のどのアミノ酸がD25の結合にとって重要であるかをさらに決定するために、D25によって中和され得ない一連のモノクローナル抗体耐性変異体(MARM)の作製を報告する。
MARM A1 Fタンパク質配列(配列番号12)
D25 MARMの中和アッセイ
単離されたD25 MARMを試験するためにRSVマイクロ中和アッセイを行った。この試験は、細胞ベースのELISAアッセイであり、このアッセイでは、感染HEp−2細胞を野生型又は変異Fタンパク質の発現に対して染色し、抗体の結合について試験した。
HR1及びSKエピトープの作製
実施例5で言及したように、D25の結合に重要な同定された領域は、C末端から、タンパク質の融合プロセスに重要なFタンパク質の規定HR1までである。従って、HR1領域(図1B)を含む構築物を、D25の結合を試験するために作製した。
D25はHR1領域よりもSKエピトープにより強く結合する
D25のSKエピトープに対する結合親和性とHR1領域に対する結合親和性とを比較するために、バイオレイヤー干渉分析を行った。D25を、1.5625nM〜100nMの範囲の濃度で抗ヒトIgG Fc捕捉センサに適用した。センサをキネティックバッファーに移して基準値を設定し、次いで、HR1断片又はSKエピトープ構築物のいずれかを含むウェルに移した。
Claims (20)
- 配列番号7のアミノ酸1〜34又は配列番号9のアミノ酸1〜34のうちの少なくとも6つのアミノ酸を含む、呼吸器合胞体ウイルス融合(RSV F)タンパク質の表面における高次構造エピトープであって、前記エピトープを含むRSV Fタンパク質はモノクローナル抗体D25又はその抗原結合断片、変異体、類似体、もしくは誘導体によって特異的に結合されることができ、ただし前記RSV Fタンパク質は融合前高次構造であることを条件とする、高次構造エピトープ。
- 前記エピトープを含む融合前高次構造のRSV Fタンパク質が、配列番号12、配列番号13、又は配列番号14のアミノ酸配列を含むRSV Fタンパク質よりも少なくとも100倍高い親和性でモノクローナル抗体D25又はその断片、変異体、類似体、もしくは誘導体によって結合され得る、請求項1に記載の高次構造エピトープ。
- 前記エピトープが、ヒトRSV亜型A Fタンパク質の表面に存在する、請求項1又は2に記載の高次構造エピトープ。
- 前記エピトープが、ヒトRSV亜型B Fタンパク質の表面に存在する、請求項1又は2に記載の高次構造エピトープ。
- mAb D25による前記エピトープへの結合が、加熱、長期保存、固定、又は変性によって変更又は破壊される、請求項1〜4のいずれか一項に記載の高次構造エピトープ。
- 前記Fタンパク質の7残基反復配列のC末端である、請求項1〜5のいずれか一項に記載の高次構造エピトープ。
- 単離された構造であって、
(a)配列番号7のアミノ酸1〜34又は配列番号9のアミノ酸1〜34のうちの少なくとも6つのアミノ酸;及び
(b)モノクローナル抗体D25又はその抗原結合断片、変異体、類似体、もしくは誘導体
を含み、前記(a)が前記(b)に特異的に結合する、構造。 - 結晶構造である、請求項7に記載の構造。
- 単離された融合タンパク質であって、
(a)配列番号7のアミノ酸1〜34又は配列番号9のアミノ酸1〜34から実質的になるRSV Fタンパク質断片;及び
(b)ポリペプチド足場
を含み、前記融合タンパク質が、モノクローナル抗体D25又はその抗原結合断片、変異体、類似体、もしくは誘導体によって特異的に結合され得る高次構造に拘束されている、融合タンパク質。 - 前記足場が、表面露出外被タンパク質を含む、請求項9に記載の融合タンパク質。
- 前記表面露出外被タンパク質がプロテアーゼインヒビターである、請求項10に記載の融合タンパク質。
- 前記プロテアーゼインヒビターが、カボチャ属プロテアーゼインヒビターである、請求項11に記載の融合タンパク質。
- 前記プロテアーゼインヒビターが、テッポウウリ(Ecballium elaterium)トリプシンインヒビターII(EETI−II)である、請求項12に記載の融合タンパク質。
- 前記EETI−IIのインヒビターループが、配列番号7のアミノ酸1〜34又は配列番号9のアミノ酸1〜34によって置換されている、請求項13に記載の融合タンパク質。
- 配列番号5の配列を含む、請求項14に記載の融合タンパク質。
- 請求項9〜15のいずれか一項に記載の融合タンパク質をコードする単離されたポリヌクレオチド。
- 請求項16に記載のポリヌクレオチドを含む発現ベクター。
- 請求項16に記載のポリヌクレオチド又は請求項17に記載のベクターを含む宿主細胞。
- 請求項9〜15のいずれか一項に記載の融合タンパク質及び担体を含む免疫原性組成物。
- 抗RSV Fタンパク質抗体を同定するための方法であって、請求項9〜15のいずれか一項に記載の融合タンパク質に結合するが、足場のみには結合しない抗体について抗体ライブラリーをスクリーニングするステップを含む、方法。
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2020
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- 2020-03-18 CY CY20201100248T patent/CY1122937T1/el unknown
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US20020018780A1 (en) * | 2000-05-25 | 2002-02-14 | Scott Koenig | Epitope-based vaccine for respiratory syncytial virus F-protein |
JP2010528601A (ja) * | 2007-06-01 | 2010-08-26 | メディミューン リミテッド | Rsv特異的結合分子およびその製造方法 |
WO2009128951A2 (en) * | 2008-04-18 | 2009-10-22 | Vaxinnate Corporation | Compositions of respiratory synctial virus proteins and methods of use |
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"Structural basis of respiratory syncytial virus neutralization by motavizumab", NAT STRUCT MOL BIOL., vol. 17, no. 2, JPN6017045683, 2010, pages 248 - 250, ISSN: 0003690131 * |
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EP2950886A4 (en) | 2016-09-07 |
AU2014212268A1 (en) | 2015-08-20 |
RS60056B1 (sr) | 2020-04-30 |
DK2950886T3 (da) | 2020-03-23 |
EP2950886B1 (en) | 2019-12-18 |
PL2950886T3 (pl) | 2020-06-01 |
JP6450688B2 (ja) | 2019-01-09 |
PT2950886T (pt) | 2020-03-26 |
US20150366960A1 (en) | 2015-12-24 |
CN105073196A (zh) | 2015-11-18 |
HRP20200404T1 (hr) | 2020-06-12 |
AU2014212268B2 (en) | 2018-07-19 |
CA2900110A1 (en) | 2014-08-07 |
ES2778899T3 (es) | 2020-08-12 |
WO2014121021A1 (en) | 2014-08-07 |
SI2950886T1 (sl) | 2020-06-30 |
EP2950886A1 (en) | 2015-12-09 |
CN105073196B (zh) | 2020-04-07 |
LT2950886T (lt) | 2020-07-10 |
CY1122937T1 (el) | 2020-10-14 |
US10016496B2 (en) | 2018-07-10 |
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